Intermediates and process for the preparation of 12alpha-halohydrocortisone and esters thereof



tats

V ni ce lcfi 3,054,790

Patented Sept. 18, 1962 carboxylic acids (e.g., benzoic acid); the lower cycloalkamTERD/IEDIATES ig s gg FOR THE noic acids; the monocyclic aralkanoic acids (e.g., phen- PREP TEON F IZWHALOHYDROCGRTL acetic acid); the lower alkenoic acids; and the lower cyclo- SONE AND ESTERS THEREQF alkenoic acids. Josef Fried, Princeton, and Patrick A. Diassi, Westfield, More particularly, in accordance with the process of NJ assignors to Olin Mathieson Chemical Corpora- 5 this invention 12a-halohydr0c0rtisone and 21-esters theretion, New York, N.Y., a corporation of Virginia of are prepared by a method which comprises treating No Drawing. Fiied Nov. 20, 1959, Ser. No. 854,252 Claims. (Cl. 260-23955) 1IflJZfl-epoxyprogesterone with a diester of oxalic acid and an alkali metal lower-alkoxide, treating the resulting This invention relates to, and has for its object the pro dienolate of h diestel: of f fii fi vision f an improved method f converting known 10 progesterone with bromine, rearranging and reducing the steroids through a series of steps involving the prepararesultmg brfm'linated derivative yield 311 ester 9 tion of new intermediates, to physiologically active ster- 1113,1213 Qxldo Ammo) P l 3 one 21 oidal final products acid, forming the 3 pyrrohdyl derivative thereof :by re- This invention comprises the conversion of the known actlon Wlth P'Y reducing radfcal of steroid 115,12fi-epoxyprogesterone by a series of steps the 'PY Y y the acflon of alkall metal involving the preparation of new intermediates to 12ocaluminum y tTeatlng the fesultlng halohydrocortisone and esters thereof having the formula PY Y 'P With hydfolylillg CHzOR agent to split off pyrrolidine and form 11/3,12,8-oxido- A pregnadene 21 ol 3 one, acylating the latter in the 21-position, oxidizing the 17 (20)-unsaturation in the 17 position and a 20-keto group, treating the re- "-O of the resulting 21-ester to introduce an hydroxyl group suiting 115,125 oxido A -pregnene 17a, 21 dio1- lected from the group consisting of hydrogen fluoride, hy-

drogen chloride, hydrogen bromide and hydrogen iodide to yield 12ahalohydrocortisone 21-acylate and hydrolyz- 25 3,20-dione-21-acylate with a hydrogen halide reagent seing the latter to obtain the compound IZa-halohydrocortiwherein X is a halogen (i.e., fluorine, chlorine, bromine sone.

and iodine) and R is hydrogen or the acyl radical of a The process of this invention can be followed easily by hydrocarbon carboxylic acid of less than ten carbon reference to the following equations and stepwise analatoms. Among the suitable carboxylic acids there may i be named: the lower alkanoic acids (e.'g., acetic, propionic, butyric and enanthic acids); the monocyclic aryl 5 CHART I i i CH3 CHz--C O 0 (lower Br-C-(i-O O 0 (lower 5 elkyl) al y 0 =0 0 =0 i \5 l O i 0 Br i (lower-O O C-(il- (lower) 0 0 (ii I I yI) alkyl I II IIIa C 0 0 (lower elkyl) (l3 0 0 (lower alkyl) C O Oaqower O H 0 OH hi to k 10% V IV 4 CHART IContinued 3320B OH:OAcyl(or H) omolc uor H) CH O H 0 =0 1 I I l l l o o 0-. 0: 0:

VI VII VIII OHzOAcyl (or 11) IX Step I.Preparation of 2,21 -Di-(Lower Alkoxyoxalyi)- 11,9,l'2fi-Oxidoprogester0ne (II) and Sodium Dienolate Thereof Compound I, ll 3,l-epoxyprogesterone, is treated with a di-(lower alkyl)oxalate, e.g., diethyl oxalate and dimethyl oxalate, and sodium lower alkoxide, e.g., sodium methoxide, in a lower alkanol, to form the sodium dienolate of Compound II, which can be separated from the reaction mixture by precipitation by the addition of a solvent such as ether, in which the reaction product is insoluble. Compound II is obtained by neutralization (with an acid such as a mineral acid), of the disodium enolate. Upon neutralization, it precipitates and is collected by filtration and then dried.

Step II.Preparati0n of Brominated Products Illa and I111) The disodium enolate of Step I is treated at low temperatures with bromine in an anhydrous solvent. The bromine is added to the anhydrous steroid solution in a ratio of about three moles of bromine to each mole of the steroid, i.e., until the point at which the solution is no longer discolored. The solution of Compound IIIa thus prepared is flushed with nitrogen and treated as such with an alkali-metal lower alkoxide in lower alcoholic solution to effect the rearrangement to Compound lIIb which is separated from solution by precipitation with water, filtration and evaporation, in vacuo, to dryness.

Step [IL-Preparation of Methyl 11fl,12fl-0xido-A Pregnadiene-3-One-21 -Oate (IV) Compound Illb in a solution of an organic solvent is treated with a reducing agent such as zinc and acetic acid. The reaction mixture is filtered. The filtrate is evaporated to dryness and the residue is chromatographed on acid washed alumina, and the benzene soluble fraction evaporated to dryness to yield Compound IV.

Step lV.Preparati0n of Methyl 3 -(N -Pyrrolr'dyl --1 15, l2p3-0xidoA l-Pregnatriene-ZI-Oate V) Compound IV is dissolved in an organic solvent and warmed at a moderate temperature with pyrrolidine. After a short time the reaction mixture is cooled and the resulting precipitate filtered ofi, washed and then dried to yield Compound V.

Step V.-Preparati0n of 11 BJZfi-Oxido-A -Pregnadiene-21-Ol-3-One (VI) Compound V is dissolved in an inert solvent (e.g., tetrahydrofuran) and reduced with an alkali metal aluminum hydride (e.g., lithium aluminum hydride). The blocking pyrrolidyl radical is then removed by hydrolysis. The reaction mixture is neutralized and evaporated to dryness to yield Compound VI.

Step Vl.Preparation of 11fl,1Z/B-Oxido-M- -Pregnadime-21-Ol-3-One-2J-Acylate VII) Compound VI in anhydrous pyridine is treated with an acylating agent particularly an acid anhydride or an acid halide (particularly the chloride) of a hydrocarbon carboxylic acid of less than ten carbon atoms selected from the aforementioned group of acids, i.e., an acid chloride or anhydride correspondnig to R of Formula IX when R is acyl. The acylation mixture is evaporated in vacuo and the residue selectively dissolved in the organic phase of a two phase system of water and organic solvent, e.g., chloroform. The organic phase is washed and evaporated to a residue which may be further purified to yield Compound VII.

Step VII .Preparation of l 1 [3,12B-Oxid0 A Pregnenel :,21 -Dfol-3,20-Di0ne-21-Acylate (VIII) Compound VII is dissolved in an organic solvent under anhydrous conditions and then hydroxylated at the 17oz, (20) unsaturation with a suitable hydroxylating reagent, among which there can be named osmium tetroxide and hydrogen peroxide in a solvent such as tertiary butanol. The residue, i.e., the partially deacylated derivative of Compound VIII, is recovered from the neutralized reaction mixture by solvent extraction and is obtained in dry form by evaporation under vacuo. It is then acylated by the action of pyridine with either an acid halide or anhydride as in Step VI to yield Compound VIII which can be recovered by extraction in a two phase aqueous system, acidification of the separated organic phase and evaporation to dryness.

Step VlH.Preparation of 12a-Halohydrocortisone-ZI- Ester (IX) Compound VIII is dissolved in a dry organic solvent, e.g., chloroform and/or tetrahydrofuran, which is inert to the action of dry hydrogen halide. The solution is cooled to below freezing temperatures and treated with a consisting of hydrogen fluoride, hydrogen bromide, hydrogen iodide and hydrogen chloride, thereby splitting the oxido radical and yielding 21-ester of 12oc-halo-hydrocortisone. The thus prepared halohydrin i.e., the compound of Formula IX, is recovered from the neutralized reaction mixture by extraction, crystallization and evapporation in vacuo. It is readily converted to the free 21- 01 with a reagent capable of hydrolyzing the 21-ester, such as dilute potassium carbonate, and the 21-01 readily recovered from the hydrolysis mixture by evaporation and recrystallization.

The compounds of Formula IX, disclosed in Serial No. 788,246, filed October 23, 1958, are physiologically active steroids which possess glucocorticoid as well as mineralocorticoid activity. Thus, they may be administered instead of and in the same manner as cortisone or hydrocortisone in the treatment of rheumatoid arthritis and dermatomyositis, or in the same manner as desoxycorticosterone in the treatment of Addisons disease or adrenal insufiiciencies, the dosage for such administration being dependent on their relative activities.

The following examples are presented to further illustrate this invention.

EXAMPLE I Preparation of 2,21 -Diethoxyoxalyl-Z15,125-xid0progesterone (II) and Sodium Dienolate Thereof To a solution of 2.00 g. (6.09 mmols.) of 115,125- oxidoprogesterone in 250 ml. of dry benzene is added 6.1 ml. (40 mmols.) of diethyloxalate and 6.3 ml. (12.8 mmols.) of 2.04 N sodium methoxide in methanol. The mixture is stirred overnight at room temperature, and then 300 ml. of anhydrous ether is added. After stirring for 30 minutes the precipitated sodium dienolate of 2,21- diethoxyoxalyl 115,125 oxidoprogesterone is filtered, Washed with ether and dried. Yield: 3.42 g.

Neutralization of an aqueous solution of the sodium dienolate by dilute hydrochloric acid precipitates 2,21- diethyloxalyl-115,125-oxidoprogesterone which is collected by filtration, washed with water and dried.

EXAMPLE II Preparation of 2,21,21-Tribromo 2,21 Diethoxyoxalyl- 115,125 Oxidoprogesterone (III) and Methyl 2- Bromo-l15,125-0xido-A Pregnadiene 3 One- 21-Oate (IIIb) To a solution of 9.11 g. (15.9 mmols.) of the sodium enolate of 2,21-diethoxyoxalyl-115,125-oxidoprogesterone in 300 m1. of methanol, 1.8 ml. (31.8 mmols.) of glacial acetic acid and 4.90 g. (62 mmols.) of anhydrous sodium acetate is added. The solution is cooled to 0 C. in an ice bath and then titrated with a solution 7.5 g. (46.8 mmols.) of bromine in 75 ml. of methanol to produce 2,21,21-tribromo-2,21-diethoxyoxalyl 115,125 oxidoprogesterone. The solution is then flushed with nitrogeen and 51.5 ml. (97.4 mmols.) of 1.89 N sodium methoxide inmethanol is added and the mixture stirred under nitrogen at room temperature for 2 /2 hours. It is then poured into 1 l. of cold 1% sodium chloride solution. The precipitated methyl 2-brorno-l15,125-oxido-A pregnadiene 3- one-21-oate is filtered, washed with water and dried.

EXAMPLE III Preparation of Methyl 115,125-0xia'o M11790) Pregnadiene-3-One-21-Oate (IV) To the residue of Example II, i.e., Compound III is added acetic acid (57 ml.) and zinc dust (3.8 g.) and the mixture is stirred at room temperature for an additional 40 minutes. It is filtered, the zinc washed with methanol and the combined filtrate and washings evaporated to dryness, in vacuo. The residue is distributed between 500 ml. each of chloroform and water. The chloroform is then washed successively with 5% NaI-ICO and twice with water and evaporated to dryness in vacuo.

This residue (5.7 g.) is dissolved in 200 m1. of benzene gives material which on crystallization from acetone-hexane yields 1.87 g. of methyl 115,125-oxido-A -pregnadiene-3-one-21-oate of the following properties: M.P. about 169-171 C.; [a] +184 (chlf.);

N 235 m =23,500 W 5.84, 6.01, 6.10 and 6.21

max. mux.

Analysis.Calcd. for C H O N (409.55); C, 76.24; H, 8.61; N, 3.42. Found: C, 75.76; H, 8.67; N, 3.72.

EXAMPLE IV Preparation of Methyl 3- (N-Pyrrolidyl) -115,125-0xid0- A -Pregnatriene-Z]-0ate (V) To a solution of 119 mg. (0.336 mmols.) of methyl 115,125-oxido-A -pregnadiene-one-21oate in 2 ml. of methanol is added 0.2 ml. of pyrrolidine, and the mixture is warmed under nitrogen for 5 minutes. On cooling, the crystalline methyl 3-(N-pyrrolidyl)-l15,125- oxido-A -pregnatriene-Zl-oate separates out. It is filtered, washed with a little cold methanol and dried. Melting point about 165-167" C.;

122,2? 226 m (6 =16,600), 277 Inn (6 18,300); 1, 1,2 ,3 5.92, 6.07, 6.15, 6.25, 12.135.

EXAMPLE V Preparation of 1 15,125-0xido-A -Pregnadiene- 21-0l-3-0ne (VI) To a solution of 1.78 g. (4.35 mmols.) of methyl 3- (N-pyrrolidyl) 115,125 oxido A -pregnatriene- 21-oate in 12 ml. of tetrahydrofuran, freshly distilled from lithium aluminum hydride, 140 mg. (3.57 mmols.) of lithium aluminum hydride is added and the reaction left at room temperature for 1 hour. Twenty-five milliliters of an acetic acid (4-ml.)-sodium acetate (4 g.) bufier in methanol (50 ml.) and water (10 ml.) are added and the mixture refluxed under nitrogen for 2 hours. After cooling the mixture is diluted with ml. each of chloroform and water. The aqueous phase is acidified with 2 N HCl, the chloroform layer separated, washed succes sively with 5% NaHCO twice with water and evaporated to dryness to yield 1.39 grams of Compound VI.

EXAMPLE VI Preparation of 1 15,125-Oxido-A -Pregnadiene- .21-0l-3-one-21-acetate (VII) properties: M.P. about 178181 C.; [a] -|148 (chlf.);

X222? 238 m (e=14,700); REX? 5.76, 5.99 and 6.19

AnaZysis.-Calcd. for C H O (370.47): C, 74.56; H, 8.16. Found: C, 74.41; H, 8.37.

EXAMPLE VII Preparation of 1 15,125-0xid0-A -Pregnene-1 7 0;,21 -di0l- 3,20 Dione-21 -Acetate (VIII) To a solution of 298 mg. (0.804 mmols.) of 115,125- oxido-A -pregnadiene-21-ol-3,20-dione 21-acetate in 15 ml. of dry tertiary butanol, there is added 0.2 ml. of pyridine and 0.7 ml. of a solution of osmium tetroxide in dry t-butanol (6 mg./ ml.). While stirring, 2.3 ml. of a 0.875 M solution of hydrogen peroxide in dry t-butanol is added dropwise over a 10 minute period. The reaction is then left at room temperature for-4 hours during which time it first darkens and then lightens and finally becomes cloudy. Nitrogen is bubbled through the reaction mixture of 15 minutes and a solution of 300 ring. of sodium sulfite in 15 ml. of water, which previously also had been nitrogenated for 15 minutes, is added. After 5 minutes under nitrogen, the mixture is neutralized with 10% acetic acid and diluted with 100 ml. of water. It is then extracted with 100 ml. and 50 ml. portions of chloroform and the combined chloroform extracts are washed twice with water, dried over sodium sulfate and evaporated to dryness to give the deacylated derivative of VIII. The residue is dissolved in 5 ml. of pyridine and 2 ml. of acetic anhydride and left at room temperature overnight. The reagents are then removed in vacuo, and the residue distributed between chloroform and water. The chloroform extract is washed successively with 2 N HCl, 5% NaHCO twice with water and then evaporated to dryness. The residue on crystallization from acetone-hexane gives 150 mg. of 115,12,8-oxido-A -pregnene-17a,21-diol-3,20-dione ZI-acetate; M.P'. about 245247;

7x223? 238 m (e=10,000); h2g1? 2.95, 5.71, 5.79, 6.04

and 611p.

Analysis.-Calcd. for C H O (402.47): C, 68.63; H, 7.51. Found: C, 68.85; H, 7.61.

EXAMPLE VIII Preparation of 12a Fluoro-M-Pregnene-I15,1 7a,21-tri0l- 3,20-Dine-21 -Acemte (12a-Fluorohydrocorzisone 21- Acemte) (IX) and Free 21-01 (a) 50 mgs. of 1lfi,l2fi-oxido-A -pregnene-l7u,21-diol- 3,20-dione-2l-acetate are dissolved in a mixture of ml. of chloroform and 2.5 ml. of dry tetrahydrofuran contained in a polyethylene bottle and the solution cooled to 80 C. by means of an acetone-Dry Ice bath. To this there is pipetted slowly with stirring 2.0 m1. of hydrogen fluoride by means of a polyethylene pipette. The reaction mixture is maintained at '-80 for minutes and then the acetone-Dry Ice bath is replaced by an ice-salt bath. The reaction temperature is maintained at -10 of 6 hours. It is then pipetted into a. stirred mixture of 50 ml. of chloroform and 50 m1. of ice water in a polyethylene beaker and carefully neutralized with sodium bicarbonate. The chloroform is separated, washed with water, dried over sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane gives 17 mg. of IZa-flIJOIOhYdIOCOIliSOHC 21-acetate melting at about 228-229" C. and having [ec.] +106 (chit);

mm 3.00, 5.75, 5.85 and 6.07;.

Analysi.r.-Calcd. for C H O F (422.48): C, 65.39; H, 7.39. Found: C, 65.22; H, 7.27.

(b) Preparation of 12lx-flu0r0hydr0c0rtisone. To a solution of 17 mg. of IZa-flUOIOhYdIOCOl'tISODC 21-acetate in 6 ml. of methanol (oxygen free) 0.9 ml. of 10% potassium carbonate is added and the mixture kept under nitrogen at room temperature for 30 minutes. It is then neutralized with dilute acetic acid, diluted with water and extracted with ethyl acetate. The ethyl acetate extracts are washed with Water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Crystallization of the residue from acetone-hexane gives 10 mg. of 12afluorohydrocortisone.

8 EXAMPLE IX Preparation of IZa-Chlorohydrocortisone 21 Acetate A solution of 20 mg. of 11 6,l2B-oxido-A -pregnene-l7 m ,2l-diol-3,20-dione 21-acetate in 5.0 ml. chloroform is cooled to 0 C. and to this there is added dropwise 0.8 ml. of a 0.51 N solution of hydrogen chloride in chloroform. After one hour at 0 the solution is diluted with water and neutralized with dilute sodium bicarbonate. The chloroform is separated, washed with Water and evaporated to dryness. Crystallization of the residue from acetone-hexane gives 11.5 mg. of 12wchlorohydrocortisone acetate, M.P. (about) 255-256, [a] (ethanol).

Anal.--Calcd. for C H O Cl (438.93): C, 62.93; H, 7.12. Found: C, 62.71; H, 7.16.

EXAMPLE X Preparation of 12a-Chlorohydrocortisone 20 mgs. of 12a-chlorohydrocortisone 21-acetate are suspended in 2 ml. of 0.27 N perchloric acid in methanol and the mixture shaken overnight at room temperature during which time the compound dissolves. The solution is neutralized with dilute sodium bicarbonate and then diluted with water. The crystals which separate are filtered, washed with water and dried to give 10 mg. of 12achlorohydrocortisone.

The invention may be variously embodied within the scope of the appended claims.

What is claimed is:

1. 2,8,21-di-(lower alkoxyoxalyD-l1,3,12B-oxidoprogesterone. I

2. The dialkali metal-dienolate of 2,21-di-(lower alkoxy oxalyl)-l16,12B-oxidoprogesterone.

3. 2fi,2l,2l-tribrorno-2,21-di-(lower alkOxyoxalyD-llfi, l2fi-oxidoprogesterone.

4. Lower alkyl 25-bromo-l16,12 3-oxido-A -pregnadiene-3-o rte-2 1 -oate.

5. Lower alkyl 11,9,1Zfi-oxido-A -pregnadiene-3- one-21-oate.

6. Lower alkyl 3-(N-pyrrolidyl)-116,12,6-oxido-A -pregnatriene-21-oate.

- 7. 115,12,8-oxido-A -pregnadiene-Z1-ol-3-one.

8. 11B,l2,8:oxido-A -pregnadiene 21-ol-3-one-21- acylate wherein the acyl radical is the acid radical of a hydrocarbon carboxylic acid of less than ten carbon atoms.

9. The process for the preparation of the compound of claim 6 which comprises treating the compound of claim 5 with pyrrolidine.

10. The process for the preparation of a compound of claim 8 which comprises reducing the 3-pyrrolidyl derivative of claim 6 with an alkali metal aluminum hydride to form the corresponding 21-01, treating the latter with an acidic hydrolyzing agent to split off pyrrolidine and recovering the 11B,12,8-0xido-A -pregnadiene-21-ol-3-one thus formed.

References Cited in the file of this patent UNITED STATES PATENTS Hogg et al. Apr. 30, 1957 Poos et al Oct. 15, 1957 OTHER REFERENCES 

1. 2B,21-DI(LOWER ALKOXYOXALYL)-11B,12B-OXIDOPROGESTERONE. 